• 2009 Turning Point

    Blocking the Path

    A second line of defense against HER2-positive breast cancer
    by Robert Levy

    Thomas Roberts and Jean ZhaoResearch led by Thomas Roberts, PhD, and Jean Zhao, PhD, suggests that some patients could benefit from drugs that block PI3 kinases. 

    Able to lock onto a key protein on the surface of some breast cancer cells, the drug trastuzumab (Herceptin) heralded a new generation of "targeted" therapies when it received federal approval in 1998. Unfortunately, cancer is often a moving target.

    In about 20 percent of breast cancer cases, the tumor cells have an oversupply of a protein called HER2. For women with such "HER2-positive" tumors, trastuzumab can literally be a lifesaver. By binding to HER2, the drug prevents it from transmitting growth signals into the cell, slowing or reversing tumor growth. Combined with chemotherapy, the drug shrinks or controls tumors in 75-80 percent of women with HER2-positive metastatic breast cancer.

    Even in these patients, however, the benefits of trastuzumab are far from permanent. Patients with the most advanced disease generally have a 10- to 14-month period in which their condition improves or stays stable, after which it begins to worsen, although some patients do well for many years.

    "It's as though HER2-positive cancers are speeding down a highway. Trastuzumab cuts them off for a while, but the tumors have a way of finding off-ramps that enable them to get around the blockade," says Eric Winer, MD, director of the Breast Oncology Center within Dana-Farber's Women's Cancers Program (WCP). "There's a growing scientific and clinical consensus that even when the cancer progresses, Herceptin is still providing a benefit, so the drug resistance is only partial.

    "We're beginning to understand what's taking place at a molecular level to enable these tumors to escape the full effect of the drug," he continues. "What's exciting is that there are a host of drugs in preliminary clinical trials that appear to have very clear activity against Herceptin-resistant cancers." (See A project to bank on.)

    Molecular maneuvers

    Scientists have discovered that when HER2-positive breast cancer cells become resistant to trastuzumab, proteins called PI3 kinases become activated within the cells. The kinases are a family of enzymes – proteins that spark chemical reactions – first studied by Thomas Roberts, PhD, co-chair of Dana-Farber's Department of Cancer Biology, and Lewis Cantley, PhD, of Beth Israel Deaconess Medical Center and a member of the Dana-Farber/Harvard Cancer Center.

    The PI3 kinases usually take their cues from the HER2 protein. HER2 is a "receptor" that juts from the cell surface like a catcher's mitt waiting for a growth molecule. The "grow" command is passed along a chain of proteins, including PI3 kinases, to the cell's central command. When HER2 is shut down by trastuzumab, abnormal PI3 kinases can sometimes get activated, transmitting growth signals on their own. The result, in a tumor, is a resurgence of cell division.

    Dr. Roberts and his colleague Jean Zhao, PhD, have developed colonies of HER2-positive cells whose growth is hobbled by trastuzumab. When they inserted a defective, or mutated, version of a PI3 kinase, the cells became trastuzumab-resistant. "Mutations to PI3 kinases may explain why some patients with HER2-positive cancers don't respond to trastuzumab, and why patients who initially respond to the drug eventually relapse," Dr. Roberts comments.

    The discovery suggests that some patients could benefit from drugs that block PI3 kinases. Dana-Farber's Geoffrey Shapiro, MD, PhD, is leading a clinical trial of such drugs; the second round of trials will test the drugs specifically in trastuzumab-resistant breast cancers.

    Downstream proteins

    The PI3 kinases aren't the only proteins in the HER2 pathway that have attracted scientists' interest. Among those at the tail end of the route is the protein NF-kß, which revs up cell growth and pushes it past all internal stop signs. A cell with a blocked HER2 receptor but an active NF-kß molecule will divide as many times as it can. Because it acts almost directly on the cell's reproductive machinery, NF-kß is suspected as a cause of "global resistance," in which breast cancers fail to respond to any current therapy.

    "We're using laboratory cell lines to test whether 'core agents' like NF-kß are responsible for multi-drug resistance, either by mutating or being activated improperly," says WCP Director J. Dirk Iglehart, MD, who is pursuing the research with Debajit Biswas, DSc. Several compounds have been developed that target key components of the NF-kß pathway, including the drug Velcade that has seen success in treating multiple myeloma. Further research by WCP investigators promises to reveal much about the basic elements of resistance and lay the groundwork for future therapies.

    Downstream proteins

    The PI3 kinases aren't the only proteins in the HER2 pathway that have attracted scientists' interest. Among those at the tail end of the route is the protein NF-kß, which revs up cell growth and pushes it past all internal stop signs. A cell with a blocked HER2 receptor but an active NF-kß molecule will divide as many times as it can. Because it acts almost directly on the cell's reproductive machinery, NF-kß is suspected as a cause of "global resistance," in which breast cancers fail to respond to any current therapy.

    "We're using laboratory cell lines to test whether 'core agents' like NF-kß are responsible for multi-drug resistance, either by mutating or being activated improperly," says WCP Director J. Dirk Iglehart, MD, who is pursuing the research with Debajit Biswas, DSc. Several compounds have been developed that target key components of the NF-kß pathway, including the drug Velcade that has seen success in treating multiple myeloma. Further research by WCP investigators promises to reveal much about the basic elements of resistance and lay the groundwork for future therapies.

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  • Clinical trials for new HER2-positive breast cancer therapies

    • The success, and limitations, of trastuzumab for HER2-positive breast cancer have inspired the creation of a series of novel drugs. Investigators in the Women's Cancers Program (WCP) are leading or offering clinical trials of five classes of these new therapies. read more 
     

    A project to bank on

    • TTo learn whether breast cancers leave telltale signs of themselves in the bloodstream, researchers need to examine samples of tumor tissue – several thousand of them, ideally. read more